There are several important reasons for studying the cellular and molecular mechanisms underlying the behavioral effects of repeated psychostimulant administration. First, abuse of psychostimulants such as cocaine is a major medical and social problem. Studies suggest that the neurophysiological adaptations associated with repeated psychostimulant administration contribute to drug craving. Second, the cellular changes underlying repeated psychostimulant administration are a form of neuronal plasticity. Studying the psychostimulant-induced neuronal adaptations will shed more light on the mechanisms of neuronal plasticity in general. Third, studying the molecular adaptations associated with psychostimulant exposure will help us to understand the neural mechanisms that lead to subjective experiences such as pleasure and pain, one of the most fascinating problems in the field of neuroscience. Growing evidence indicates that the neurotrophin family of growth factors plays an important role in the effects of psychostimulants. BDNF and NT-3 microinjections into the VTA have been shown to enhance the behavioral activating effects of cocaine. The goal of the research outlined in this proposal is to expand on these findings by studying the role of BDNF and NT-3 receptors, trkB and trkC respectively, in cocaine-induced behavioral sensitization. Specifically, this will be accomplished in the following two stages. First, rats will be injected with acute and repeated systemic injections of cocaine and levels of trkB and trkC protein in the ventral tegmental area (VTA) will be measured. Second, trkB and trkC receptors will be up-regulated and down-regulated in the VTA using sense and antisense recombinant adenovirus vectors. Following virus treatment, rats will be given acute and repeated systemic cocaine injections. Subsequent behavioral activity will be measured and the VTA will be excised to test for changes in tyrosine hydroxylase activity as a measure of cocaine-induced neuronal plasticity.